Nuclear hormone receptors (NHRs) are major regulators of hormone-responsive breast and prostate cancers, and they function as targets for endocrine therapies and as biomarkers having very significant prognostic and predictive values. The overall goal of this project is to advance positron emission tomographic (PET) imaging of specific nuclear hormone receptors and receptor function to improve the management and treatment of breast and prostate cancer patients. While some PET imaging agents have been developed by us for the estrogen receptor (ER) and the androgen receptor (AR), the current status of PET imaging of NHR levels and function in breast and prostate cancer is rather underdeveloped, and many opportunities lie ahead. Our current aims are to: (1) Develop a Progesterone Receptor (PR) PET imaging hormone-challenge test to improve prediction of success of endocrine therapy in breast Cancer. Two PR PET imaging agents, the [18F]FFNP and [18F]FPTP will be studied in xenografts and murine mammary tumor models of ER-positive endocrine-sensitive and endocrine-resistant breast cancer. Hormone treatment protocols will be developed to optimize a 1-day estradiol challenge test for ER function, based on an acute change in PR-PET, to obtain a rapid, accurate and robust prediction of breast cancer hormone responsiveness. (2) Evaluate Fluorine-18 labeled ligands for the Peroxisome Proliferator-Activated Receptor gamma (PPAR?) as PET imaging agents of predictive value for prostate cancer recurrence. PPAR? levels measured by IHC in a nested case-control human prostate cancer tissue array resource will be examined for their predictive power for risk of recurrence. The uptake efficiency and selectivity of two F-18 labeled PPAR? ligands will be studied in preclinical models of prostate cancer to develop PPAR? PET imaging protocols for suspected primary prostate cancer that can distinguish aggressive from indolent disease and improve prediction of the risk of disease recurrence. (3) Design PET imaging agents for the Estrogen Related Receptor alpha (ERR?) to develop a novel ERR? PET-Imaging test of prognostic and predictive value in hormone-responsive and unresponsive breast cancer. Fluorine-substituted analogs of high affinity ERR? ligands will be prepared and labeled with fluorine-18 rapidly, at high specific activity. Their biodistribution will then be evaluated in preclinical models of ERR?-positive breast cancers to develop ERR? as a predictive marker for novel therapies for both ER-positive and negative breast cancers.